US5780579A - Method for the preparation of polyamino acids - Google Patents

Method for the preparation of polyamino acids Download PDF

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Publication number
US5780579A
US5780579A US08/592,299 US59229996A US5780579A US 5780579 A US5780579 A US 5780579A US 59229996 A US59229996 A US 59229996A US 5780579 A US5780579 A US 5780579A
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alcohol
amount
ncas
water
polymerization
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Gerard Soula
Jean-Michel Grosselin
Rafael Jorda
Catherine Castan
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Flamel Technologies SA
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Flamel Technologies SA
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24

Definitions

  • the present invention belongs in the technical field of the synthesis of polyamino acids from amino acid N-carboxyanhydrides (referred to hereinbelow as NCAs).
  • the present invention relates to the polymerization, in liquid medium, of NCAs by polymerization initiators of strong base type.
  • Polyamino acids are biocompatible and biodegradable polymers which find applications in the biomedical field.
  • they may constitute biomaterials which are useful, for example, as starting materials for the manufacture of prostheses and implants or alternatively for use as supports which allow the release of active principles.
  • Applications of polyamino acids as resorbable suture threads, as temporary skin substitutes or as textile fibers have also been described.
  • the polyamino acids In order to be usable in these various applications, it is important for it to be possible for the polyamino acids to be in a liquid or semi-liquid form, which can be handled in the context of operations for forming finished articles, such as the formation of films, spinning, molding, etc. This therefore implies control of the intrinsic viscosity and/or of the weight-average molar mass M w of the polyamino acid synthesized.
  • NCAs are generally carried out in liquid medium, using polymerization initiators which may be protic nucleophiles, such as water, primary amines and secondary amines, or strong bases, such as alkoxides or tertiary amines or phosphines. Besides these strong bases, English sic! patent GB-996,760 proposes organometallic reagents such as trialkyllithiums or trialkylaluminums as NCA polymerization initiators.
  • polymerization initiators may be protic nucleophiles, such as water, primary amines and secondary amines, or strong bases, such as alkoxides or tertiary amines or phosphines.
  • strong bases such as alkoxides or tertiary amines or phosphines.
  • English sic! patent GB-996,760 proposes organometallic reagents such as trialkyllithiums or trialkylaluminums as NCA polymerization
  • Kricheldorf specifies (page 92) that the polymerization of NCAs, initiated by protic nucleophiles, does not give rise to high molecular weights (DPn less than 200), in contrast with initiators of the strong base type which give access to polymers of DPn greater than 200. Since these polymers are precisely those which prove to be suitable for the applications of the polyamino acids, initiation of the polymerization of NCAs by strong bases has thus been the synthetic route adopted by those skilled in the art.
  • one of the essential aims of the present invention is to provide a method for the synthesis of polyamino acids from NCA, in liquid medium and in the presence of initiators of strong base type:
  • the Applicant has, to its credit, been able to demonstrate that in order to achieve this aim, inter alia, the polymerization of the NCAs should, against all expectation, be carried out in a liquid reaction medium comprising, in particular, water and/or an alcohol.
  • GB patent 996,760 teaches that the use of infinitesimal amounts of water, 10 -2 % by weight relative to the solvent, causes an increase in the reduced viscosity of the final polymer: 3.5 to 4.32 (Examples 1-2).
  • the present invention relates to a method for the preparation of polyamino acids, with controlled molecular weights, by polymerization of N-carboxyanhydrides (NCAs) of at least one amino acid, using at least one initiator of the strong base type and in liquid medium,
  • NCAs N-carboxyanhydrides
  • the alcohol it is preferably selected from linear or cyclic C 1-24 monoalcohols and/or dialcohols, or from aromatic alcohols and, more preferably, from the following list: methanol, ethanol, propanol, butanol, hexanol, phenols, glycols, these compounds being used alone or as a mixture with each other.
  • the alcohol used as a means of adjusting the reduced viscosity, and thus the molecular mass, of the finished polymer may be employed at a proportion of from 0 to 3000 mol %, preferably of from 10 to 1000 mol % and, even more preferably, of from 10 to 500 mol % relative to the NCAs.
  • the water it may be employed at a proportion of from 0.1 to 50% by weight relative to the rest of the liquid medium, preferably at a proportion of from 0.5 to 10% by weight and, even more preferably, of from 1 to 5% by weight.
  • a subsidiary advantage associated with the use of water and/or alcohol is the acceleration of the rate of polymerization.
  • the liquid medium comprises an organic cosolvent.
  • the starting materials for the method according to the invention are N-carboxyanhydrides of amino acids of L, D or racemic L+D configuration. Such a starting material may be a mixture of various enantiomers and/or racemates. It is possible to use monomers of only one type consisting of an NCA of a given amino acid, or alternatively different monomers consisting of NCAs of distinct amino acids, so as to form a copolymer.
  • amino acid NCAs may be prepared by any known and suitable technique such as, for example, that described by W. H. Daly et al., Tetrahedron Letters, Vol. 29, No. 6, p 5859, (1988).
  • the precursors of these NCAs may be chosen from the following amino acids, alone or as a mixture: from glycine, alanine, phenylalanine, leucine, isoleucine, valine, ⁇ -aminoisobutyric acid, aspartic acid, glutamic acid, ⁇ -aminoadipic acid, ornithine, lysine, arginine, cysteine, methionine, threonine, serine, tyrosine.
  • the concentration of the NCA monomer in the reaction medium is advantageously between 1 and 40% by weight relative to the organic solvent and preferably between 2 and 20% by weight and, even more preferably, between 4 and 15% by weight.
  • the initiator is chosen from tertiary amines and/or phosphines.
  • polymerization initiators characteristic of the invention mention may be made, for example, of triethylamine, trimethylamine, tris-N-propylamine, triisopropylamine, tributylamine, tricyclohexylamine, 4,4',4"-tris(dimethylamino)triphenylmethane and tertiary phosphines: triphenylphosphine, trimethylphosphine, dimethylphenylphosphine, tributylphosphine, triisopropylphosphine, tricyclohexylphosphine and diphenylmethylphosphine.
  • triethylamine is used as initiator.
  • the initiator represents a molar amount of between 0.001 and 1 molar, preferably of between 0.005 and 0.1 molar, relative to the NCA.
  • the polymerization is performed in liquid medium, which means, in other words, that it may be performed in solution or in suspension.
  • the organic cosolvent(s) used is (are) chosen from the following chemical classes: cyclic or linear ethers, nitriles, halogenated aliphatics, aromatics, halogenated aromatics, nitro derivatives, esters, ketones, amides, sulfones, sulfoxides, or mixtures thereof.
  • the organic cosolvent is chosen from alkanes: pentane, hexane, octane or decane, for example, and fluoroalkanes, or mixtures thereof.
  • Halogenated aliphatic hydrocarbons which may be mentioned, for example, are chloroform, dichloromethane, 1,2-dichloromethane sic!, 1,1-dichloroethane, 1,2-dichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, trichloroethylene, tetrachloroethylene, 1,1,2,2-tetrachloroethane, 1,1,1,2-tetrachloroethane, pentachloroethane, 1,2-dichloropropane, 2,2-dichloropropane, 1,3-dichloropropane, 1,2,3-dichloropropane, dichloroomethane sic!, 1-bromo-3-chloropropane, isobutylene bromide and bromoform.
  • the cyclic ethers may be e.g. dioxane or tetrahydrofuran.
  • Acetonitrile is an example of a nitrile
  • toluene and xylene are examples of aromatics
  • nitromethane is an example of a nitro derivative
  • methyl acetate is an example of an ester.
  • Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) are respectively examples of an amide and of a sulfoxide which may be used.
  • An example of a sulfone which may be mentioned is sulfolane.
  • dioxane is among the particularly preferred organic solvents.
  • this polymerization reaction takes place at normal atmospheric pressure, in ambient atmosphere and with a reaction medium temperature of between -20° C. and +150° C., preferably of between +10° and +90° C.
  • This method gives access to polyamino acids (polymers, copolymers) whose molar masses and reduced viscosity are controllable. This control is achieved without it hampering the ease of use or the economy of the method.
  • FIG. 1 shows the variation in reduced viscosity of the polymer as a function of the water added to the polymerization medium.
  • FIG. 2 represents a variation of the rate constant k for the polymerization reaction, as a function of the amount of water in the reaction medium, in the polymerization according to Example 1.
  • FIG. 3 illustrates the decrease in viscosity of the copolymer as a function of the amount of water added to the reaction medium.
  • FIG. 4 represents the kinetic profile for disappearance of the NCAs, monitored by infrared, in the polymerization according to Example 4.
  • the reduced viscosity which is a standard method of characterization of polyamino acids, is measured with a solution in trifluoroacetic acid (TFA) at a concentration C of 0.5 g/l.
  • TFA trifluoroacetic acid
  • the reduced viscosity reflects the weight-average molar mass M w of the polyamino acids, as shown in Example 4 below.
  • the poly-Glu(OMe) is isolated by precipitation in 2 l of demineralized water at room temperature and washed twice with 500 ml of water, before being dried, in the presence of phosphorus pentoxide under water vacuum, to constant weight. 3.63 g of Glu(OMe) polymer are obtained, i.e. a yield of 95%.
  • the reduced viscosity of the copolymer, measured in trifluoroacetic acid, is 3.54 dl/g.
  • FIG. 1 attached shows the variation in reduced viscosity of the polymer as a function of the water added to the polymerization medium.
  • FIG. 2 attached represents the variation of the rate constant k for the polymerization reaction as a function of the amount of water in the reaction medium. This provides evidence of the beneficial effect of water on the kinetics for the polymerization of Glu(OMe)-NCA.
  • the Glu(OMe)-NCA and Leu-NCA mixture (5 g of 47 mol % Leu-NCA) and distilled dioxane (75 ml) are successively introduced into a 250 ml reactor, flushed beforehand with nitrogen.
  • the polymerization reactor is placed in an oil bath maintained at 40° C. and the reaction medium is stirred at 65 rev/min (the temperature of the reaction medium is 38° C.).
  • the triethylamine (0.029 g) is added rapidly.
  • the viscous mixture is diluted with 75 ml of dioxane and the stirring is increased to 150 rev/min, so as to solubilize the polymer rapidly.
  • the Leu/Glu(OMe) copolymer is isolated by precipitation in 2 l of demineralized water at room temperature and washed twice with 500 ml of water, before being dried under vacuum in the presence of phosphorus pentoxide. 3.53 g of Leu/Glu(OMe) copolymer are thus obtained, i.e. a yield of 95%.
  • the reduced viscosity of the copolymer, measured in trifluoroacetic acid, is 3.7 dl/g.
  • the amount of water present in the reaction medium was studied between 0.1% and 10% by weight relative to the dioxane.
  • Table 2 summarizes the characteristics of the copolymer by adding increasing amounts of water to the reaction medium.
  • FIG. 3 attached illustrates the decrease in viscosity of the copolymer as a function of the amount of water added to the reaction medium.
  • the aim of this series of copolymers is to vary the reduced viscosity of the copolymers and to keep their composition constant.
  • the monomer proportions adopted are 53% of GluOMe and 47% of leucine.
  • the polar solvent used is absolute ethanol.
  • the amount of absolute ethanol was varied between 21 and 458 mol % relative to the NCAs (i.e. 0.5 and 8.5% by weight/dioxane); the proportions of monomers introduced remained constant.
  • Example 2 was repeated, leaving out the triethylamine and adding an amount of water equal to 10% by weight of the dioxane.
  • the reaction medium is then treated in the same way as in the case of a standard polymerization.
  • This comparative test shows that water, used alone without initiator, leads to the formation of a copolymer of low molar mass.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Polyamides (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Materials For Medical Uses (AREA)
  • Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
US08/592,299 1993-08-10 1994-08-09 Method for the preparation of polyamino acids Expired - Fee Related US5780579A (en)

Applications Claiming Priority (3)

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FR9309991 1993-08-10
FR9309991A FR2708932B1 (fr) 1993-08-10 1993-08-10 Procédé de préparation de polyaminoacides.
PCT/FR1994/000992 WO1995004772A1 (fr) 1993-08-10 1994-08-09 Procede de preparation de polyaminoacides

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EP (1) EP0713505B1 (de)
JP (1) JP3499559B2 (de)
AT (1) ATE208406T1 (de)
DE (1) DE69429002T2 (de)
ES (1) ES2169081T3 (de)
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003070808A1 (de) * 2002-02-19 2003-08-28 Bayer Chemicals Ag Polyaminosäuren und verfahren zu deren herstellung
US20030211976A1 (en) * 2002-03-07 2003-11-13 Andreasen Kasper Huus Polyamino acid-based particle insulin formulation
US20040005999A1 (en) * 2002-03-07 2004-01-08 Andreasen Kasper Huus Polyamino acid-based particle insulin preparation
US20040038885A1 (en) * 2000-10-06 2004-02-26 Nathan Bryson Colloidal suspension of submicronic particles for carrying active principles and their mode of preparation
US20040138095A1 (en) * 2001-04-02 2004-07-15 Gerard Soula Colloidal suspension of nanoparticles based on an amphiphilic copolymer
US20050037077A1 (en) * 2001-10-09 2005-02-17 Valerie Legrand Galenic microparticulate oral formulation for delayed and controlled release of pharmaceutical active principles
US20060110463A1 (en) * 2002-04-09 2006-05-25 Catherine Castan Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin
US20060172914A1 (en) * 2005-01-04 2006-08-03 Kurt Breitenkamp Synthesis of hybrid block copolymers and uses thereof
US20070065478A1 (en) * 2002-06-21 2007-03-22 Advanced Cardiovascular Systems Inc. Polycationic peptides for cardiovascular therapy
US7226618B1 (en) 1999-11-23 2007-06-05 Flamel Technologies, Inc. Colloidal suspension of submicronic particles as vectors for active principles and method for preparing same
US20070160568A1 (en) * 2002-07-30 2007-07-12 Flamel Technologies, Inc. Polyamino acids functionalized by at least one hydrophobic group and the therapeutic application thereof
US20070196497A1 (en) * 2003-11-21 2007-08-23 Flamel Technologies, Inc. Pharmaceutical formulations for the prolonged release of active principle(s) and their applications
US20070265192A1 (en) * 2003-10-03 2007-11-15 Soula Remi Telechelic Homopolyamino Acids Functionalized with Hydrophobic Groups, and Their Applications, Especially Therapeutic Applications
US7683024B2 (en) 2002-06-07 2010-03-23 Flamel Technologies Polyaminoacids functionalized by alpha tocopherol and uses thereof, particular for therapeutic applications
US7906145B2 (en) 2002-04-09 2011-03-15 Flamel Technologies Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US20110124840A1 (en) * 2005-02-11 2011-05-26 Kurt Breitenkamp Synthesis of Homopolymers and Block Copolymers

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ290975B6 (cs) * 1998-06-05 2002-11-13 Ústav Makromolekulární Chemie Av Čr Funkcionalizované polymery alfa-aminokyselin a způsob jejich přípravy
FR2885130B1 (fr) * 2005-04-28 2007-06-29 Centre Nat Rech Scient Procede de preparation de polylysines dendrimeres greffes
CA2656077C (en) * 2006-06-15 2014-12-09 Marc Mckennon A process for the preparation of poly-alpha-glutamic acid and derivatives thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB996760A (en) * 1962-09-28 1965-06-30 Asahi Chemical Ind A process for polymerising n-carboxy- -amino acid anhydrides
GB1024393A (en) * 1963-03-30 1966-03-30 Asahi Chemical Ind Process for polymerizing n-carboxy-ª‡-amino acid anhydrides
GB1202765A (en) * 1967-07-20 1970-08-19 Kyowa Hakko Kogyo Kk PROCESS FOR THE POLYMERIZATION OF alpha-AMINO ACID-N-CARBOXY ANHYDRIDES
US3536672A (en) * 1968-10-04 1970-10-27 Kyowa Hakko Kogyo Kk Process for the polymerization of alpha-amino acid - n - carboxy anhydrides using imidazole initiators

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB996760A (en) * 1962-09-28 1965-06-30 Asahi Chemical Ind A process for polymerising n-carboxy- -amino acid anhydrides
GB1024393A (en) * 1963-03-30 1966-03-30 Asahi Chemical Ind Process for polymerizing n-carboxy-ª‡-amino acid anhydrides
GB1202765A (en) * 1967-07-20 1970-08-19 Kyowa Hakko Kogyo Kk PROCESS FOR THE POLYMERIZATION OF alpha-AMINO ACID-N-CARBOXY ANHYDRIDES
US3536672A (en) * 1968-10-04 1970-10-27 Kyowa Hakko Kogyo Kk Process for the polymerization of alpha-amino acid - n - carboxy anhydrides using imidazole initiators

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7226618B1 (en) 1999-11-23 2007-06-05 Flamel Technologies, Inc. Colloidal suspension of submicronic particles as vectors for active principles and method for preparing same
US20080015332A1 (en) * 2000-06-10 2008-01-17 Flamel Technologies, Inc. Colloidal suspension of submicronic particles for carrying active principles and their mode of preparation
US7270832B2 (en) 2000-10-06 2007-09-18 Flamel Technologies, Inc. Colloidal suspension of submicronic particles for carrying active principles and their mode of preparation
US20040038885A1 (en) * 2000-10-06 2004-02-26 Nathan Bryson Colloidal suspension of submicronic particles for carrying active principles and their mode of preparation
US7709445B2 (en) 2001-04-02 2010-05-04 Flamel Technologies Colloidal suspension of nanoparticles based on an amphiphilic copolymer
US20040138095A1 (en) * 2001-04-02 2004-07-15 Gerard Soula Colloidal suspension of nanoparticles based on an amphiphilic copolymer
US20050037077A1 (en) * 2001-10-09 2005-02-17 Valerie Legrand Galenic microparticulate oral formulation for delayed and controlled release of pharmaceutical active principles
US20050119445A1 (en) * 2002-02-19 2005-06-02 Thomas Geller Polyamino acids and method for producing the same
WO2003070808A1 (de) * 2002-02-19 2003-08-28 Bayer Chemicals Ag Polyaminosäuren und verfahren zu deren herstellung
US20060148676A1 (en) * 2002-03-07 2006-07-06 Novo Nordisk A/S Polyamino acid-based particle insulin formulation
US20050233968A1 (en) * 2002-03-07 2005-10-20 Novo Nordisk A/S Polyamino acid-based insulin preparation
US20070190159A1 (en) * 2002-03-07 2007-08-16 Novo Nordisk A/S Polyamino acid-based insulin preparation
US20040005999A1 (en) * 2002-03-07 2004-01-08 Andreasen Kasper Huus Polyamino acid-based particle insulin preparation
US20030211976A1 (en) * 2002-03-07 2003-11-13 Andreasen Kasper Huus Polyamino acid-based particle insulin formulation
US20060110463A1 (en) * 2002-04-09 2006-05-25 Catherine Castan Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin
US9814684B2 (en) 2002-04-09 2017-11-14 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US7910133B2 (en) 2002-04-09 2011-03-22 Flamel Technologies Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin
US7906145B2 (en) 2002-04-09 2011-03-15 Flamel Technologies Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US10004693B2 (en) 2002-04-09 2018-06-26 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US7683024B2 (en) 2002-06-07 2010-03-23 Flamel Technologies Polyaminoacids functionalized by alpha tocopherol and uses thereof, particular for therapeutic applications
US7217426B1 (en) * 2002-06-21 2007-05-15 Advanced Cardiovascular Systems, Inc. Coatings containing polycationic peptides for cardiovascular therapy
US20070065478A1 (en) * 2002-06-21 2007-03-22 Advanced Cardiovascular Systems Inc. Polycationic peptides for cardiovascular therapy
US7901703B2 (en) 2002-06-21 2011-03-08 Advanced Cardiovascular Systems, Inc. Polycationic peptides for cardiovascular therapy
US7803394B2 (en) * 2002-06-21 2010-09-28 Advanced Cardiovascular Systems, Inc. Polycationic peptide hydrogel coatings for cardiovascular therapy
US20070160568A1 (en) * 2002-07-30 2007-07-12 Flamel Technologies, Inc. Polyamino acids functionalized by at least one hydrophobic group and the therapeutic application thereof
US7678882B2 (en) 2002-07-30 2010-03-16 Flamel Technologies Polyamino acids functionalized by at least one hydrophobic group and the therapeutic application thereof
US20070265192A1 (en) * 2003-10-03 2007-11-15 Soula Remi Telechelic Homopolyamino Acids Functionalized with Hydrophobic Groups, and Their Applications, Especially Therapeutic Applications
US7659365B2 (en) 2003-10-03 2010-02-09 Flamel Technologies Telechelic homopolyamino acids functionalized with hydrophobic groups, and their applications, especially therapeutic applications
US8084045B2 (en) 2003-11-21 2011-12-27 Flamel Technologies Pharmaceutical formulations for the prolonged release of active principle(s) and their applications
US20070196497A1 (en) * 2003-11-21 2007-08-23 Flamel Technologies, Inc. Pharmaceutical formulations for the prolonged release of active principle(s) and their applications
US7601796B2 (en) 2005-01-04 2009-10-13 Intezyne Technologies, Inc. Synthesis of hybrid block copolymers and uses thereof
US8268936B2 (en) 2005-01-04 2012-09-18 Intezyne Technologies, Inc. Synthesis of hybrid block copolymers and uses thereof
US20110021718A1 (en) * 2005-01-04 2011-01-27 Intezyne Technologies Synthesis of hybrid block copolymers and uses thereof
US20060172914A1 (en) * 2005-01-04 2006-08-03 Kurt Breitenkamp Synthesis of hybrid block copolymers and uses thereof
US20110124840A1 (en) * 2005-02-11 2011-05-26 Kurt Breitenkamp Synthesis of Homopolymers and Block Copolymers

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JP3499559B2 (ja) 2004-02-23
DE69429002D1 (de) 2001-12-13
EP0713505B1 (de) 2001-11-07
DE69429002T2 (de) 2002-08-14
ES2169081T3 (es) 2002-07-01
ATE208406T1 (de) 2001-11-15
WO1995004772A1 (fr) 1995-02-16
FR2708932A1 (fr) 1995-02-17
FR2708932B1 (fr) 1995-11-10
EP0713505A1 (de) 1996-05-29
JPH09504560A (ja) 1997-05-06

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